This application is a continuation-in-part of application Ser. No. 320,773, filed Nov. 12, 1981, now U.S. Pat. No. 4,582,855, issued Apr. 15, 1986.
Compounds of the present invention are useful because of their valuable pharmaceutical properties. They exhibit .beta.-adrenergic blocking activity and are also useful in the treatment of glaucoma.
The present invention also relates to the treatment or prophylaxis of cardiac disorders. More particularly, the invention relates to a novel method of treatment or prophylaxis of cardiac disorders which comprises administration of .beta.-adrenergic blocking agents and to compounds useful in such method.
The therapeutic and prophylactic uses of compounds which block sympathetic nervous stimulation of .beta.-adrenergic receptors in the heart, lungs, vascular system and other organs are well documented. Typically, such compounds are administered therapeutically to patients suffering from ischemic heart disease or myocardial infarction for the purpose of reducing heart work, i.e., heart rate and contractile force. Reducing heart work reduces oxygen demand, and may also actually increase oxygen supply. Thus reducing heart work can aid in the prevention of further tissue damage and can relieve angina pectoris.
.beta.-Adrenergic stimulation may also aggravate or cause arrhythmias because of increased levels of catecholamines. Thus .beta.-blocking agents may be employed to reduce the risks of arrhythmias.
Some of the compounds of the present invention selectively block .beta.-adrenergic receptors in various organs. .beta.-receptors in the heart are generally referred to as .beta..sub.1 receptors, and those associated with vasodilation and bronchodilation are .beta..sub.2 receptors. Selective .beta.-blockers are preferred for the treatment of cardiac disorders, because they may have less potential to cause hypertension or bronchoconstriction. A number of .beta..sub.1 selective adrenergic blocking agents have been discovered [Smith, L. H., J. Appl. Chem. Biotechnol., 28, 201-202 (1978)]. Most such compounds are structural variations of 1-amino-3-aryloxy-2-propanol.
Heretofore, the emphasis in .beta.-blocker research has been to develop compounds which can be administered to cardiac patients over long periods of time. However, often it is desirable to the critical care setting to quickly reduce heart work or improve rhythmicity during a cardiac crisis, e.g., during or shortly after a myocardial infarction. Conventional .beta.-blocking agents can be employed for such treatment, but their duration of action may be much longer than desired by the physician. A .beta.-blocking agent possessing a long duration of action does not allow precise control of heart work or prompt reversal of the .beta.-blocking effect, which may be required in a critical care setting. For instance, if heart output becomes dangerously low, it is desirable to quickly reduce or eliminate .beta.-blocking activity. The lingering activity of available .beta.-blocking agents can be counterproductive and can greatly complicate the therapeutic decisions required of the physician during such critical care of cardiac patients.
Accordingly, there is a need for a pharmaceutical preparation and method of treatment, employing a .beta.-adrenergic blocking agent having a short duration of action.
Compounds of the present invention are novel .beta.-blocking agents. The presence of the ester function in these compounds provides for predictable metabolism of these compounds to metabolites which are inactive as .beta.-blockers and are highly polar and readily excreted.
Some of the compounds of the present invention are metabolized rapidly after infusion into the systemic circulation and, therefore, have a short duration of .beta.-blocking action. Such compounds are particularly advantageous since they allow precise control during treatment of certain cardiovascular diseases by intravenous administration of the compound.
Compounds of the present invention are also useful for the treatment of glaucoma or lowering of intraocular pressure by topical administration of the compounds to the eye. Compounds with short duration in the systemic circulation, but with good stability in ocular fluid, are particularly useful since they have a low potential for producing systemic side effects.
Glaucoma is a condition of the eye characterized by increased intraocular pressure. Untreated, the condition can eventually lead to irreversible retinal damage and blindness. Conventional therapy for glaucoma has involved topical administration of pilocarpine and/or epinephrine, administered to the eye several times daily.
The use of various .beta.-blocking agents to lower intraocular pressure is well documented. For example, U.S. Pat. No. 4,195,085 to Stone discloses a method for treatment of glaucoma by the optical administration of a .beta.-blocking compound, timolol maleate. U.S. Pat. No. 4,127,674 discloses a method of treating glaucoma with labetalol, a known antagonist of both alpha and beta adrenergic receptors. However, these methods also possess significant drawbacks, in that the absorption of the .beta.-blocking compound into the systemic circulation can cause undesirable side effects. Such side effects result from prolonged .beta.-blocking action on the heart, bronchioles and blood vessels. For example, according to Physician's Desk Reference, Charles E. Baker, Jr., 35th Edition, 1981, p. 1233, adverse reactions to the topical use of timolol maleate can include bronchospasm and heart failure, as well as cardiac conduction defects. Accordingly, there is a need for a method of treatment for glaucoma or for lowering intraocular pressure which is relatively free of unwanted systemic side-effects.